Evaluation of Tobramycin and Ciprofloxacin as a Synergistic Combination Against Hypermutable Pseudomonas Aeruginosa Strains via Mechanism-Based Modelling.

Vanessa E Rees,Jürgen B Bulitta,Roger L Nation,Cornelia B Landersdorfer,Antonio Oliver

doi:10.3390/pharmaceutics11090470

Abstract

Hypermutable Pseudomonas aeruginosa strains have a greatly increased mutation rate and are prevalent in chronic respiratory infections. Initially, we systematically evaluated the time-course of total and resistant populations of hypermutable (PAO∆mutS) and non-hypermutable (PAO1) P. aeruginosa strains in 48-h static concentration time-kill studies with two inocula. Both strains were exposed to clinically relevant concentrations of important antibiotics (aztreonam, ceftazidime, imipenem, meropenem, tobramycin, and ciprofloxacin) in monotherapy. The combination of tobramycin and ciprofloxacin was subsequently assessed in 48-h static concentration time-kill studies against PAO1, PAO∆mutS, and two hypermutable clinical P. aeruginosa strains. Mechanism-based mathematical modelling was conducted to describe the time-course of total and resistant bacteria for all four strains exposed to the combination. With all monotherapies, bacterial regrowth and resistant populations were overall more pronounced for PAO∆mutS compared to PAO1. The combination of tobramycin and ciprofloxacin was synergistic, with up to 106.1 colony forming units (CFU)/mL more bacterial killing than the most active monotherapy for all strains, and largely suppressed less-susceptible populations. This work indicates that monotherapies against hypermutable P. aeruginosa strains are not a viable option. Tobramycin with ciprofloxacin was identified as a promising and tangible option to combat hypermutable P. aeruginosa strains.

Highlights

Respiratory infections caused by Pseudomonas aeruginosa are a major cause of morbidity and mortality among patients with cystic fibrosis (CF) [1]
The current study systematically compared the antibacterial effects of monotherapy with a range of antibiotics having different mechanisms of action; we examined the time-course of bacterial counts and emergence of resistant populations of non-hypermutable and hypermutable P. aeruginosa
In addition we assessed the tobramycin and ciprofloxacin combination against four strains, including two hypermutable clinical strains. This is the first study to have characterised the time-course of bacterial killing, regrowth and emergence of resistance of hypermutable PAO∆mutS against multiple antibiotics over 48 h

Summary

Introduction

Respiratory infections caused by Pseudomonas aeruginosa are a major cause of morbidity and mortality among patients with cystic fibrosis (CF) [1]. Hypermutable P. aeruginosa strains are prevalent in chronic respiratory infections of CF patients [2,3]. The impact of increased spontaneous mutation rates found in hypermutable P. aeruginosa on the time-course of bacterial killing, regrowth, and resistance emergence over 48 h has not been systematically evaluated for a range of antibiotics from different classes. We aimed to assess the synergistic properties and suppression of resistant populations by the combination of two fast-acting antibiotics with different mechanisms of action, tobramycin and ciprofloxacin, against hypermutable and non-hypermutable P. aeruginosa, including two clinical hypermutable strains. The time-courses of the total and resistant populations after exposure to this antibiotic combination were evaluated in 48-h static concentration time-kill experiments and subsequently described by mechanism-based mathematical modelling (MBM). The rapid-acting combination of tobramycin with ciprofloxacin was found to be a promising synergistic option to combat hypermutable P. aeruginosa

Objectives

Methods

Results

Conclusion